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Researchers Find Biological Explanation for Wheat Sensitivity

Researchers Find Biological Explanation for Wheat Sensitivity

Posted: Fri 5 Aug 2016 6:19

by RitaA

I'm so glad that research is being conducted into non-celiac gluten sensitivity. Given the high incidence (at least anecdotally) among people who have experienced a delayed diagnosis and/or treatment for Lyme disease, I can't help but wonder if Lyme disease (and possibly other infections), in combination with genetic predisposition, might be one trigger for non-celiac gluten sensitivity -- or non-celiac wheat sensitivity (NCWS) as it is referred to in these articles.

In any case, it is reassuring to know that researchers now have scientific evidence to disprove the belief (held by many medical professionals) that non-celiac gluten sensitivity simply doesn't exist.

NEW YORK, NY (July 26, 2016)—A new study may explain why people who do not have celiac disease or wheat allergy nevertheless experience a variety of gastrointestinal and extra-intestinal symptoms after ingesting wheat and related cereals. The findings suggest that these individuals have a weakened intestinal barrier, which leads to a body-wide inflammatory immune response.

Findings from the study, which was led by researchers from Columbia University Medical Center (CUMC), were reported in the journal Gut.

“Our study shows that the symptoms reported by individuals with this condition are not imagined, as some people have suggested,” said study co-author Peter H. Green, MD, the Phyllis and Ivan Seidenberg Professor of Medicine at CUMC and director of the Celiac Disease Center. “It demonstrates that there is a biological basis for these symptoms in a significant number of these patients.”

Celiac disease is an autoimmune disorder in which the immune system mistakenly attacks the lining of the small intestine after someone who is genetically susceptible to the disorder ingests gluten from wheat, rye, or barley. This leads to a range of gastrointestinal symptoms, including abdominal pain, diarrhea, and bloating.

Researchers have struggled to determine why some people, who lack the characteristic blood, tissue, or genetic markers of celiac disease, experience celiac-like GI symptoms, as well as certain extra-intestinal symptoms, such as fatigue, cognitive difficulties, or mood disturbance, after ingesting foods that contain wheat, rye, or barley. One explanation for this condition, known as non-celiac gluten or wheat sensitivity (NCWS), is that exposure to the offending grains somehow triggers acute systemic immune activation, rather than a strictly localized intestinal immune response. Because there are no biomarkers for NCWS, accurate figures for its prevalence are not available, but it is estimated to affect about 1 percent of the population, or 3 million Americans, roughly the same prevalence as celiac disease.

In the new study, the CUMC team examined 80 individuals with NCWS, 40 individuals with celiac disease, and 40 healthy controls. Despite the extensive intestinal damage associated with celiac disease, blood markers of innate systemic immune activation were not elevated in the celiac disease group. This suggests that the intestinal immune response in celiac patients is able to neutralize microbes or microbial components that may pass through the damaged intestinal barrier, thereby preventing a systemic inflammatory response against highly immunostimulatory molecules.

The NCWS group was markedly different. They did not have the intestinal cytotoxic T cells seen in celiac patients, but they did have a marker of intestinal cellular damage that correlated with serologic markers of acute systemic immune activation. The results suggest that the identified systemic immune activation in NCWS is linked to increased translocation of microbial and dietary components from the gut into circulation, in part due to intestinal cell damage and weakening of the intestinal barrier.

“A systemic immune activation model would be consistent with the generally rapid onset of the reported symptoms in people with non-celiac wheat sensitivity,” said study leader Armin Alaedini, PhD, assistant professor of medicine at Columbia. He also holds an appointment in Columbia’sInstitute of Human Nutrition and is a member of the Celiac Disease Center.

NCWS patients who followed a diet that excluded wheat and related cereals for six months were able to normalize their levels of immune activation and intestinal cell damage markers, the researchers also found. These changes were associated with significant improvement in both intestinal and non-intestinal symptoms, as reported by the patients in detailed questionnaires.

Dr. Alaedini added, “The data suggest that, in the future, we may be able to use a combination of biomarkers to identify patients with non-celiac wheat sensitivity, and to monitor their response to treatment.”

The study involved an international collaboration between researchers at CUMC and the University of Bologna in Italy. “These results shift the paradigm in our recognition and understanding of non-celiac wheat sensitivity and will likely have important implications for diagnosis and treatment,” said co-author Umberto Volta, MD, professor of internal medicine at the University of Bologna. “Considering the large number of people affected by the condition and its significant negative health impact on patients, this is an important area of research that deserves much more attention and funding.”

In future studies of NCWS, Dr. Alaedini and his team plan to investigate the mechanisms responsible for triggering the intestinal damage and breach of the epithelial barrier and to further characterize the immune cell responses.

Received 31 March 2016
Revised 9 June 2016
Accepted 20 June 2016
Published Online First 25 July 2016

Abstract

Objective

Wheat gluten and related proteins can trigger an autoimmune enteropathy, known as coeliac disease, in people with genetic susceptibility. However, some individuals experience a range of symptoms in response to wheat ingestion, without the characteristic serological or histological evidence of coeliac disease. The aetiology and mechanism of these symptoms are unknown, and no biomarkers have been identified. We aimed to determine if sensitivity to wheat in the absence of coeliac disease is associated with systemic immune activation that may be linked to an enteropathy.

Design

Study participants included individuals who reported symptoms in response to wheat intake and in whom coeliac disease and wheat allergy were ruled out, patients with coeliac disease and healthy controls. Sera were analysed for markers of intestinal cell damage and systemic immune response to microbial components.

Results

Individuals with wheat sensitivity had significantly increased serum levels of soluble CD14 and lipopolysaccharide (LPS)-binding protein, as well as antibody reactivity to bacterial LPS and flagellin. Circulating levels of fatty acid-binding protein 2 (FABP2), a marker of intestinal epithelial cell damage, were significantly elevated in the affected individuals and correlated with the immune responses to microbial products. There was a significant change towards normalisation of the levels of FABP2 and immune activation markers in a subgroup of individuals with wheat sensitivity who observed a diet excluding wheat and related cereals.

Conclusions

These findings reveal a state of systemic immune activation in conjunction with a compromised intestinal epithelium affecting a subset of individuals who experience sensitivity to wheat in the absence of coeliac disease.

Significance of this study

What is already known on this subject?

Some individuals experience a range of symptoms in response to the ingestion of wheat and related cereals, yet lack the characteristic serological or histological markers of coeliac disease.

Accurate figures for the population prevalence of this sensitivity are not available, although estimates that put the number at similar to or greater than for coeliac disease are often cited.

Despite the increasing interest from the medical community and the general public, the aetiology and mechanism of the associated symptoms are largely unknown and no biomarkers have been identified.

What are the new findings?

Reported sensitivity to wheat in the absence of coeliac disease is associated with significantly increased levels of soluble CD14 and lipopolysaccharide-binding protein, as well as antibody reactivity to microbial antigens, indicating systemic immune activation.

The results demonstrate the presence of objective markers of systemic immune activation and gut epithelial cell damage in individuals who report sensitivity to wheat in the absence of coeliac disease.

The data offer a platform for additional research directed at assessing the use of the examined markers for identifying affected individuals and/or monitoring the response to treatment, investigating the underlying mechanism and molecular triggers responsible for the breach of the epithelial barrier, and evaluating novel treatment strategies in affected individuals.

From the Open Access article:

B-cell response to microbial antigens

When compared with the healthy control and coeliac disease cohorts, the NCWS group had significantly higher levels of EndoCAb IgM (p<0.0001 and p=0.028, respectively) (figure 2D), but not IgG or IgA (see figure 2C and online supplementary figure S2A). In contrast to the NCWS cohort, the coeliac disease group had higher levels of EndoCAb IgA when compared with the NCWS and healthy control groups (p=0.021 and p=0.032, respectively) (see onlinesupplementary figure S2A), but not IgG or IgM (figure 2C, D).

Furthermore, the levels of IgG and IgM antibodies to flagellin were significantly elevated in the NCWS cohort when compared with the healthy control group (p=0.001 and p=0.009, respectively) (figure 2E, F). These antibodies were not significantly elevated in the coeliac disease cohort, although there was a trend towards higher IgA reactivity to flagellin when compared with healthy controls (p=0.059) (see online supplementary figure S2B). The increased IgM antibody response to flagellin correlated with the elevated EndoCAb IgM in the NCWS cohort (r=0.386, p<0.0001) (see online supplementary figure S3).

[snip]

Discussion

As expected, the cohort of individuals with sensitivity to wheat in the absence of coeliac disease did not exhibit significantly elevated antibody responses to TG2 or deamidated gliadin sequences. This indicates that in contrast to coeliac disease, the observed humoral immune response to gluten in NCWS is independent of TG2 enzymatic activity and HLA-DQ2/DQ8, and is likely to target certain epitopes that are distinct from those in coeliac disease. We hypothesised that the enhanced antibody response to native gliadin in NCWS individuals, particularly IgG and IgM isotypes, may be a consequence of ongoing intestinal epithelial barrier defects. If so, such defects might also give rise to an inadequate regulation of the interaction between the gut microbiota and systemic circulation, resulting in peripheral immune activation. To examine this, we measured the levels of LBP and sCD14 as indicators of the translocation of microbial products, particularly LPS, across the epithelial barrier. Translocated circulating LPS can result in the rapid secretion of LBP by GI and hepatic epithelial cells, as well as sCD14 by CD14+ monocytes/macrophages.19 sCD14 binds LPS in the presence of LBP to activate TLR4.27 We found significantly elevated serum levels of both LBP and sCD14 in individuals with NCWS in comparison with patients with coeliac disease and healthy controls. The high degree of correlation between serum LBP and sCD14 suggested that these molecules are concurrently expressed in response to the stimulus in NCWS individuals.

We also quantified serum levels of antibody to LPS core oligosaccharide, or EndoCAb, which is known to modulate in response to bacterial endotoxin in circulation.28 As they are involved in the neutralisation of circulating endotoxin, EndoCAb immunoglobulins are typically depleted in response to an acute LPS exposure, but eventually rise due to the B-cell anamnestic response.19 Individuals in the NCWS cohort exhibited increased levels of EndoCAb IgM. To demonstrate that the systemic immune response in individuals identified as having NCWS would not be limited to only LPS if driven by translocated microbial products, we also measured serum levels of antibody to flagellin, the principal substituent protein of the flagellum in Gram-positive and negative bacteria. We found that levels of IgG and IgM antibodies to flagellin were significantly elevated in the NCWS cohort. Considering that no individuals in this study had evidence of infection, these observations are suggestive of a translocation of microbial products from the GI tract that contributes to the observed innate and adaptive immune activation in the NCWS cohort.

Circulating bacterial components, such as LPS and flagellin, bind to their respective TLRs on various cells, including macrophages and dendritic cells, which results in signalling through the myeloid differentiation factor 88 (MyD88) adaptor protein.27 Ultimately, MyD88 signalling leads to the activation of transcription factor nuclear factor-κB and increased expression of various proinflammatory cytokines that can exert deleterious systemic effects.19 ,29 A systemic innate immune activation model would be consistent with the generally rapid onset of reported symptoms in NCWS.6 In addition, circulating microbial products can bind to TLRs on other cells to trigger a more localised inflammatory response. For example, LPS binds directly to TLR4 on the luminal surface of brain blood vessels, resulting in local cytokine secretion in the brain that has been shown to activate the microglia to displace inhibitory synapses.30 In HIV infection, where the presence of microbial translocation is linked to intestinal epithelial damage, increased systemic immune activation in response to bacterial antigens is associated with cognitive deficits.31 Such a pathway might contribute to some of the neurocognitive symptoms experienced by NCWS individuals.

[snip]

On the other hand, despite the established extensive villous damage associated with coeliac disease, neither LBP nor sCD14 levels were found to be significantly elevated in the coeliac disease group, thus standing in stark contrast to the NCWS cohort. In addition, among the immunoglobulin responses to microbial antigens, only IgA antibodies appeared to be increased in coeliac disease. These data suggest that there is an effective mechanism for the neutralisation of microbial products that may cross into the lamina propria in most cases of coeliac disease, possibly in part via the localised IgA response and mucosal phagocytic cells. These mechanisms are known to be essential for the immune surveillance of luminal antigens and the elimination of microbial products that cross the epithelial barrier, thereby reducing the likelihood of their translocation into the submucosa and access to blood vessels.19 Such mucosal immune responses may be lacking or inadequate in individuals with NCWS. Instead, what we observed were enhanced IgM responses to gliadin, LPS and flagellin in the NCWS cohort, which clearly contrasted with the coeliac disease group.

[snip]

The hallmark of NCWS is the onset of intestinal and/or extraintestinal symptoms on ingestion of gluten-containing foods, that is, wheat, rye and barley, and the alleviation of symptoms on their withdrawal from diet. To determine whether the patient-reported symptom resolution on the elimination of these foods would be associated with the amelioration of intestinal epithelial cell damage and a reduction in microbial translocation and systemic immune activation, we examined the above markers in a subset of NCWS subjects before and after a diet that excluded wheat and related cereals. The results indicated a significant decline in the markers of immune activation and gut epithelial cell damage, in conjunction with the improvement of symptoms. However, the magnitude of change in the measured biological markers did not correlate significantly with that for the symptom scores. This appears to be similar to observations in patients with coeliac disease, where symptoms are known to be a poor predictor of disease activity and associated biomarkers.46 ,47 A limitation of this portion of the study was the absence of a healthy control group to assess the potential impact of the dietary restriction in unaffected individuals.

In summary, the results of this study on individuals with sensitivity to wheat in the absence of coeliac disease demonstrate (1) significantly increased serum levels of sCD14 and LBP, as well as antibody reactivity to microbial antigens, indicating systemic immune activation; (2) an elevated expression of FABP2 that correlates with the systemic immune responses to bacterial products, suggesting compromised intestinal epithelial barrier integrity and increased microbial translocation; and (3) a significant change towards normalisation in the levels of the immune activation markers, as well as FABP2 expression, in response to the restrictive diet, which is associated with improvement in symptoms. Our data establish the presence of objective markers of systemic immune activation and epithelial cell damage in the affected individuals. The results of the multivariate data analysis suggest that a selected panel of these may have use for identifying patients with NCWS or patient subsets in the future. It is important to emphasise that this study does not address the potential mechanism or molecular trigger(s) responsible for driving the presumed loss of epithelial barrier integrity and microbial translocation. Further research is needed to investigate the mechanism responsible for the intestinal damage and breach of the epithelial barrier, assess the potential use of the identified immune markers for the diagnosis of affected individuals and/or monitoring the response to specific treatment strategies, and examine potential therapies to counter epithelial cell damage and systemic immune activation in affected individuals.

Re: Researchers Find Biological Explanation for Wheat Sensitivity

Posted: Fri 5 Aug 2016 7:04

by RitaA

I agree completely with this quote from an article/blog entry about gluten sensitivity published in 2014:

Modern medicine is really good at crisis intervention…[but] they don’t do well with chronic issues”

As it stands, the existence of NCGS has neither been proven nor disproven by anyone. But gluten sensitivity sits at the intersection of several dilemmas in medicine today and, unlike how it’s portrayed in the media, is hardly an all-or-nothing affair. Proving it wrong will not instantly heal the people who have prescribed themselves a gluten-free diet. Proving it wrong will not produce a cure for IBS, a shorter time to a celiac diagnosis, or the correct way to handle potential celiac disease. Neither will proving it right. In the eyes of one gluten avoider, “Modern medicine is really good at crisis intervention…[but] they don’t do well with chronic issues”.2

[snip]

Oddly, many participants from the second Monash study opted to continue their gluten-free diet after the study ended because the diet made them “feel” better.5 This intrigued the researchers, so they invited the participants back for a third study to find out whether gluten was affecting their mental state.5 This trial proceeded along the same lines as the second, and mental state was assessed using the Spielberger State Trait Personality Inventory. Gluten still had no impact on gastrointestinal symptoms, but it did induce feelings of depression. This is a very interesting result because it could explain the lure of the gluten-free diet; however, researchers are still a long way off from uncovering a definite link between gluten and depression, transient or otherwise.

[snip]

Where do we go from here?

In a large Australian survey from 2013, roughly 7% of respondents had diagnosed themselves with gluten sensitivity.30 The gluten free fad is just as popular in Australia as it is in the US,30, 31 so this figure might also estimate the prevalence of gluten sensitivity here, even though a 2009 estimate was much lower at 0.55%.32

Who might be in the 7%? Some with IBS, some with a botched celiac diagnosis, some with potential celiac disease, some who are intolerant to foods that they inadvertently eliminated because of their new diet, some who get only a psychological benefit from avoiding gluten, some whose symptoms continue despite their best efforts, some who really are hypochondriacs, and perhaps some with NCGS as its own entity. It doesn’t even matter whether non-celiac gluten sensitivity exists — these people will remain.

But it’s going to be a while until gluten sensitivity is understood. According to Dr. Alessio Fasano, director of the Center for Celiac Research at the Massachusetts General Hospital, NCGS stands where celiac disease stood 40 years ago.8 Even so, all we need are a few good DBPCFC trials to answer the basic question as to whether gluten sensitivity exists. This may be easier said than done, however, as the Monash group found such a strong nocebo effect in their trials that they now believe that future research should involve IBS sufferers who have not tried a gluten-free diet before.33

In the meantime, more people will suspect that they are sensitive to gluten, and if they are not to be lost to self-diagnosis or alternative medicine, the medical community must be able to lead them through the process of sorting out their suspicions. The Monash researchers have suggested an interim pathway for diagnosing gluten sensitivity, which includes:4

. The adequate exclusion of celiac disease.
. The exclusion of other dietary triggers, like FODMAPs or other foods suspected by the individual.
. A gluten-free diet, if symptoms did not resolve or improve in Step 2.
. Blinded gluten challenges, if symptoms did improve in Step 3.
. Rechallenges with gluten to establish their gluten threshold.[/list]

As a clinical approach, this moves us away from thinking about gluten sensitivity in all or nothing terms and addresses the issues one person at a time.

The author

Laurie Laforest, PhD is a former materials scientist turned computer programmer turned food intolerance mom. She blogs at foodconnections.org to clear up misconceptions on the nature, the prevalence, and the diagnosis of food intolerance.

Re: Researchers Find Biological Explanation for Wheat Sensitivity

Posted: Fri 5 Aug 2016 7:22

by RitaA

And here's an even earlier article/blog entry from 2012 mentioning non-celiac gluten sensitivity:

What’s been lost in an enthusiasm for gluten avoidance, is the fact that there are some people who do experience undesirable symptoms from gluten consumption, but don’t have celiac disease. It’s this group that was the focus of a recent paper in the Annals of Internal Medicine: Nonceliac Gluten Sensitivity: Sense or Sensibility? It’s behind a paywall, but I’ll try to summarize the paper in the context of what we know, and what we don’t know, about celiac disease and possible non-celiac gluten sensitivity.

Celiac disease

Celiac disease (CD) is an autoimmune disease, not an allergy or intolerance. The disease manifests with inflammation and injury to the bowel lining when gluten is consumed. It can cause gastrointestinal scarring and villous atrophy – resulting in permanent damage. While it normally presents with gastrointestinal symptoms, symptoms can also manifest as conditions like skin rash.The disease has been described as protean, which is appropriate. A 2001 survey of patients with confirmed celiac disease indicated patients reported symptomatic disease an average of 11 years before a diagnosis was reached. A similar survey of pediatric patients suggested a similar trend: Multiple physicians and other diagnoses. By manifesting in so many different ways, it cannot be diagnosed based on symptoms alone. So why is it so difficult to identify? It isn’t – but you need to look for it.

The immunologic response in celiac disease is a reaction to gliadin, a protein found in wheat, barley and rye. A highly effective test is now widely available. Blood is tested for IgA antibody human recombinant tissue transglutaminase (IgA-tTGA) or endomysium (IgA-EMA). These tests are both highly sensitive (90%–96%) and specific (>95%) for celiac disease. Positive results are followed by biopsy, necessary to establish a diagnosis. That diagnosis is confirmed by evaluating the effectiveness of a gluten-free diet on reported symptoms. (The full diagnostic workup is nicely summarized in the AGA Institute Medical Position Statement on the Diagnosis and Management of Celiac Disease.) Given the availability of a sensitive and specific test for celiac disease, there has been some discussion on whether widespread and routine screening for celiac disease should occur. The evidence and risk/benefit currently suggests screening in the absence of any symptoms is still unwarranted.

Non-celiac Gluten Sensitivity

We have a sensitive and specific test for celiac disease, so diagnosis should be straightforward, right? If you have celiac disease, you must avoid gluten for life. But what about those that test negative for celiac disease, but have symptoms from eating gluten-containing foods? There are at least five possible scenarios:

> You could be IgA deficient, in which case there’s a false negative. Other laboratory tests may be done, and compared with the biopsy.
> You may already be on a gluten-free diet, which will cause a false negative result.
> It could simply be a false negative laboratory test result (no laboratory test is 100% sensitive and specific).
> There may be some form of subclinical CD present (not yet established as fact, but plausible)
> It may not be celiac disease, and other causes need to be evaluated.

It’s this last category, deemed non-celiac gluten sensitivity (NCGS) which is the subject of the recent Annals paper. Despite the identification of NCGS over 30 years ago, it’s only recently that interest seems to have exploded – I count about 336,000 Google results, but only 10 results in PubMed. Remarkably, the Annals paper points out that the public awareness of NCGS exceeds that of celiac disease [PDF].

So how do we distinguish between the CD and NCGS, objectively? Here the Annals paper includes a nice table which summarizes the challenge:

[Table]

It is the protean nature of CD that makes NCGS seem so prevalent. As there’s a myriad of non-specific symptoms that could signal true CD, any any of these symptoms can also be attributed to NCGS. So what high-quality evidence exists to establish NCGS is real? Not a lot, yet. The Annals paper identifies only a single placeb0-controlled rechallenge trial, which concluded that NCGS “may exist”. There is a lack of systematic research, but lots of opinions. A recent essay [PDF] from Sapone et al in Biomed Central used a consensus-based approach to evaluate NCGS and other gluten-related disorders. It concludes by labeling gluten “toxic”, declaring celiac disease an “epidemic”, and suggesting that the prevalence of gluten sensitivity will continue to increase, supposedly because of a lack of adaptive response to deliberate changes bred into wheat strains.

But is that accurate? There are no accurate prevalence estimate for NCGS – because there are no objective signs or symptoms that can be evaluated. Given the magnification of fears of gluten among the general population, I suspect prevalence will increase simply because of perceived health concerns and rank fearmongering over gluten: nocebo effects, where an inert substances causes negative symptoms. From a scientific perspective a few possible mechanisms that have been postulated for NCGS, none of which have been established yet:

> a stress response, rather than an immune response, which is unlikely given the varied manifestations of NCGS
> an IgE-mediated reaction to wheat flour, possibly to another chemical compound it contains
> starch malabsorption
> opioid-like effects of gluten on the colon (opioid receptors in the gastrointestinal tract are the reason narcotics cause constipation)
> some degree of low-grade inflammation, possibly signalling some sort of subclinical CD, presenting in a way that cannot be diagnosed with the current tests

Conclusion

The idea that gluten sensitivity is real and widespread goes far beyond the current scientific evidence, and the well-established facts of celiac disease. Time will tell if gluten avoidance follows the path of Candida, and other dietary fears and fads that preceded it. But it doesn’t need to. Given the protean nature of CD, symptoms cannot be dismissed as nocebo effects: A CD diagnosis needs to be ruled out before NCGS is even contemplated. Going gluten-free in the absence of a proper medical evaluation may not be directly harmful, but it complicates a diagnosis. Moreover, it can be expensive, and difficult to maintain 100% avoidance – essential with CD, but not established as necessary with NCGS. Besides, who really wants to cut out all gluten-containing products if they don’t need to? Until better diagnostic criteria are established, the N of 1 trial is probably the most science-based (if impractical) approach: single-blind challenges to measure for subjective or objective symptoms. Our challenge in dealing with dietary fads as health professionals is to recognize that some of our patients are suffering, and evaluate them in a science based way: without dismissing the symptoms, and without advocating dietary transformations that may be unnecessary.

Re: Researchers Find Biological Explanation for Wheat Sensitivity

Posted: Sat 6 Aug 2016 3:54

by velvetmagnetta

Wow, Rita...Thank you for putting all of this information together! (It is so nice to read you again!)

I had no idea that people with gluten sensitivity (who do not have Celiac's) were thought to be imagining or "making-up" their symptoms. What is up with doctors thinking people are faking illnesses?

Doctors or other cynics who think this way really need to do some actual scientific studies to find out what percentage of the population are hypochindriacs - instead of just assuming this nonsense just because they don't feel like putting in the effort to help soemone with non-standard symptoms.

Sorry - I got a little off-topic there!

Re: Researchers Find Biological Explanation for Wheat Sensitivity

Posted: Sat 6 Aug 2016 4:03

by RitaA

I think I may have posted this previously in another thread, but it's a good reminder of how some (and possibly most) people with gluten sensitivity were dismissed by medical professionals in the past. Hopefully with more research and education of medical professionals, along with newer tests, people with non-celiac gluten sensitivity will get an earlier diagnosis and relief of their symptoms with dietary changes.

As one couple from New York State discovered, untreated gluten sensitivity can affect your gut, your skin… and your brain.

By Alicia Woodward

[Updated June 27, 2016]﻿

[snip]

A Gluten Brain Invasion

Mike Howell, 53, is a solid, consistent kind of guy, a hard-working man devoted to his wife and kids. Steady and reliable both as a family man and an employee, Howell, of Sodus, New York, worked as a stationary engineer for Eastman Kodak for 25 years, operating and maintaining industrial boilers. He rarely missed a day at the job and always showed up on time. Yet within weeks of the episode at church, Linda noticed that her steadfast husband was changing in alarming ways.

“He would have spells where he would forget how to get to work," she says. "He couldn’t spell his name. It was very scary. I knew we were in trouble.”

Howell visited his primary care doctor, Jeannine Dolan, M.D., and then a neurologist. After examinations, more tests and an MRI, doctors found white matter lesions on his brain but no evidence of a stroke.

“The neurologist wasn’t sure what was going on,” Linda says.

By the end of January, the doctor was calling Howell “a mystery man.” He suggested a psychiatric exam and recommended a psychotherapy group.

In the meantime, Howell was suffering from violent headaches that didn’t respond to any of the usual over-the-counter remedies. “He was in so much pain that he would grab the back of his head and hold it,” Linda says. “Nothing we did would stop it.”

“The left side of my body was numb. I just didn’t feel right,” Mike recalls.

By the end of March, Linda could barely control her frustration and concern. The more the doctor talked about Howell’s “psychological problems,” the angrier she became. “I’d been married to this man for over two decades and I knew this wasn’t psychological,” she says. Sitting in the doctor’s office one day, her temper exploded.

“I totally lost it. I was so angry that I was shouting at the doctor and crying. He looked over at Mike and said, ‘It doesn’t look like your wife is handling this very well.'”

They never went back.

The Long Road to Gluten Sensitivity Diagnosis

A visit to a second neurologist provided no additional insight. By June, Linda took Howell to a third neurologist who conducted more tests, including a spinal tap, another MRI and an additional psychiatric exam to evaluate him for depression and memory loss. He was tested for Mad Cow Disease (Bovine Spongiform Encephalopathy, BSE), Multiple Sclerosis (MS) and other neurologic conditions.

Howell continued to suffer from debilitating headaches but now he had episodes of face droop and slurred speech.

“It was like he was drunk, like his mouth was full of novocaine,” Linda says.

Howell would have periods where he didn’t recognize Linda or their children. “There was no rhyme or reason to it. He would be completely out to lunch, have no idea where he was or who I was … and then it would go away,” Linda says.

In early December, Howell was diagnosed with Binswanger Disease, a rare and progressive form of dementia that is characterized, among other things, by memory and cognition losses and difficulty in walking and speaking. There is no cure. For the Howells, it was a devastating death sentence.

“Mike was given five years to live,” Linda says.

Already grieving the loss of the strong husband she loved and now faced with his inevitable slow decline with no hope for recovery, Linda mourned deeply. To honor their life together and celebrate the vibrant years they had had, as well as the limited time still remaining, the Howells decided to renew their wedding vows. They planned a summer ceremony and invited friends and their extended family.

“The family was all there," Linda says. "They came in from all over. Our sons and grandson walked me down the aisle. It was wonderful.”

Gluten: the Unassuming Culprit

As the months progressed, Howell continued visiting doctors for various tests and ongoing treatments. Additional MRIs revealed more white matter lesions in his brain. He underwent chelation therapy to address heavy metals in his blood due to working in an industrial environment. As his symptoms worsened, he became increasingly dependent and began using a wheelchair. Settling down for the long haul, Linda quit her job in order to take care of him full-time.

In October 2004, Howell was referred to yet another doctor for a consult—Heidi Schwarz, M.D., a neurologist at the University of Rochester Medical Center and assistant professor of neurology at Strong Memorial Hospital. Almost immediately, the Howells sensed this doctor was different. Schwarz examined Howell, reviewed his medical history and listened intently to Linda describing her husband’s symptoms. “She never once looked at us like we were crazy,” Linda says.

“I was the fourth or fifth neurologist that Mike had seen," Schwarz says. "He had an abnormal MRI scan and risk factors for stroke. We were trying to control those risk factors … and yet he was getting worse.”

During one subsequent visit, while Schwarz was examining Howell yet again and “we were scratching our heads,” Schwarz says, “Mike’s wife happened to mention that some lab work years back had showed that Mike had a gluten problem. I said, ‘It showed what? Well, I’ll be darned!”

For confirmation, Schwarz repeated the blood test. Results revealed that Howell did, in fact, have sensitivity to gluten. With that, in January 2005, she nailed his diagnosis: gluten ataxia.

Diagnosis: Gluten Ataxia

Gluten ataxia, a disorder of the immune system, belongs to the same spectrum of gluten sensitivity as celiac disease and dermatitis herpetiformis. In these conditions, a heightened sensitivity to gluten, the protein in wheat, barley and rye, creates an increased level of allergy-fighting antibodies (specifically, antigliadin IgG and IgA) that turn on the body and attack it.

Symptoms of gluten sensitivity can be numerous and vary widely from individual to individual. Generally speaking, celiac disease is evidenced in the gut by damage to the small bowel. Dermatitis herpetiformis is evidenced on the skin by an itchy rash. With gluten ataxia, the focus of disease activity is in the brain, specifically the cerebellum, the center that controls coordination and complex movements like walking, speaking and swallowing. Often, the peripheral nerves located outside the spinal cord are also involved, leading to chronic and progressive neuropathy, a disease affecting the nervous system that results in feelings of numbness, tingling or pain.

Ataxia means clumsiness or loss of coordination. Symptoms of gluten sensitivity with neurologic manifest-ations are slurred speech, loss of coordination in upper and lower limbs, difficulty with normal walking, ocular problems, chronic headaches. It may affect the fingers and hands, the arms or legs, the body, speech or eye movements. In children and young adults, gluten ataxia can also cause developmental delay, diminished muscle tone, learning disorders and ADHD.

Recent studies indicate that gluten ataxia is a common cause of sporadic idiopathic (of unknown origin) ataxia, accounting for up to 40 percent of cases. Yet despite its prevalence, the disease isn’t well known and diagnosis is frequently missed. The reason? Doctors often look for gastrointestinal distress before they will consider the possibility of gluten sensitivity.

“Gluten ataxia is out there but so few of us have seen it—or perhaps recognized it," Schwarz says. "If you see a patient who has malabsorption problems, they can’t tolerate this or can’t tolerate that, if they have gastrointestinal complaints along with neurologic symptoms, then you order the antibody tests. Yet most patients I see with neurologic manifestations of gluten intolerance don’t have a lot of GI symptoms, if any.”

According to a 2003 study published in Brain, gastrointestinal symptoms are present in only 13 percent of patients with gluten ataxia. “It’s been estimated that for every one patient with celiac disease who presents with GI complaints, there are seven patients with celiac disease who have no GI symptoms …. Only a proportion of patients presenting with neurological dysfunction association with gluten sensitivity will also have GI symptoms.”

The bottom line is that gluten sensitivity can be primarily—and at times exclusively—a neurologic disease.

“This is a disease that’s difficult to diagnose unless you maintain a low threshold of suspicion,” Schwarz says.

The blood panel to screen for gluten ataxia is the same used to ascertain gluten sensitivity. It measures the antigliadin antibodies (IgG and IgA) circulating in the blood, along with the endomysium and tissue transglutaminase antibodies. “A small bowel biopsy is not needed if symptoms are neurologic and antibodies are positive,” Schwarz says.

“If antibody results come back positive, I’ll send the patient to a gastroenterologist to do a small bowel biopsy to check for classic changes attributable to celiac disease, but even if this is normal, I will still recommend a six-month trial on a gluten-free diet,” Schwarz says.

Research by Dr. Marios Hadjivassiliou and colleagues published in Brain in 2003 states, “.... IgG antigliadin antibodies by definition remain the best diagnostic marker for gluten ataxia.”

Gluten-Free Diet for Life

It used to be that Mike Howell’s breakfast of choice was a bowl of shredded wheat. For lunch, he’d grab a sandwich, sub or pizza. But these days, Howell stays away from his old favorites. The treatment for gluten ataxia is a strict gluten-free diet.

“I love donuts, muffins and bagels and I still would like to be able to eat this stuff,” Howell says. “But I know that if I touch any of it, I’ll end up more brain damaged.”

Linda has enthusiastically embraced all aspects of gluten-free eating, creating gluten-free pumpkin pie, bagels, and pasta for her husband. “When he gets even a quarter gram of gluten, he’ll have a problem. In less than 24 hours, there’s a massive change. He’ll look at you as you talk to him and he won’t understand what you’re saying. His legs will drag, he’ll have unsteadiness, and slurred speech,” Linda says.

“Then it takes me at least two to three days to get back to where I was,” Howell says.

After many months on the gluten-free diet, Howell has shown remarkable improvement. His progress has been slow but steady.

“Remember that this is an auto-immune disease where antibodies attack other cells in the body. Once the immune process starts, it sort of has a life of its own,” Schwarz says. “That’s why going on a gluten-free diet can take months to see an effect with these patients.”

Today, Howell is out of the wheelchair and walking on his own. His thinking has cleared. And the violent headaches he used to endure on a daily basis? “I haven’t had one since April,” he says.

Howell’s sensitivity to even trace amounts of gluten remains very high. Schwartz says this type of reaction isn’t unusual.

“If a patient’s antibody levels are up and, for example, they prepare their food on the same countertop surface as everyone else, their symptoms will return. That’s even when they’re careful not to eat anything with gluten in it,” Schwarz says. “Gluten is in a surprising number of products, like toothpaste and medicines. Whenever I put anyone with gluten sensitivity on a medication, we check with the manufacturer to make sure it’s clear.”

Schwarz’s advice for patients who have episodic neurologic symptoms with no apparent known cause? Be persistent with your medical team.

“Almost every patient I’ve seen with gluten sensitivity has been dismissed somewhere along the line with a psychological diagnosis like depression or anxiety. If a person is suspicious that they may have gluten sensitivity, they should approach their doctor with the idea that this disease is very difficult to diagnose and has a broad array of clinical manifestations,” Schwartz says. “A lot of doctors had seen Mike Howell and had said they just didn’t know. That’s what’s going to happen to these patients unless they’re persistent. You have to be comfortable in advocating for yourself. It’s the squeaky wheel that gets the oil.”

Edited to include the author's entire name.

Re: Researchers Find Biological Explanation for Wheat Sensitivity

Posted: Sat 6 Aug 2016 4:09

by RitaA

velvetmagnetta wrote:Wow, Rita...Thank you for putting all of this information together! (It is so nice to read you again!)

I had no idea that people with gluten sensitivity (who do not have Celiac's) were thought to be imagining or "making-up" their symptoms. What is up with doctors thinking people are faking illnesses?

Doctors or other cynics who think this way really need to do some actual scientific studies to find out what percentage of the population are hypochindriacs - instead of just assuming this nonsense just because they don't feel like putting in the effort to help soemone with non-standard symptoms.

Sorry - I got a little off-topic there!

Hi velvetmagnetta!

I must have been working on my post when you posted yourself. I'm so glad to see you back!

It really is disheartening to think that some doctors find it easier to accuse their patients of making things up than simply admit that modern medicine doesn't have all the answers. While it's nice to have objective data, why not simply give all patients the benefit of any doubt?

Your comment isn't off-topic in the least -- especially not in this thread.

A $200,000 grant from National Institute of Allergy and Infectious Diseases has been awarded for a study seeking to identify antibody biomarkers for ME/CFS. The Bateman Horne Center will partner with Armin Alaedini, PhD on this important research.

We know ME/CFS is a very heterogeneous condition with different causes and different constellation of symptoms. There is evidence for a least six ME/CFS subtypes and it would be important to identify and treat these various subtypes accordingly. Biomarkers can be used to identify ME/CFS biomarker subtypes and a promising biomarker is antibodies. Antibodies are proteins that our body’s immune system produces in response to things like viruses or bacteria. We also know that our immune system can produce antibodies against parts of our own cells and tissues, a potentially harmful response called autoimmunity. Our body can also produce antibodies to food proteins like wheat gluten. Antibody biomarkers could be used to delineate a viral ME/CFS subtype from an autoimmune ME/CFS subtype from gastrointestinal ME/CFS subtype.

A few years ago I started working with Armin Alaedini, PhD from Columbia University to determine if there were antibodies being produced against central nervous system proteins in ME/CFS patients but did not find any. Because some ME/CFS patients have “gut issues”, Alaedini examined whether there was a distinct intestinal immune response in ME/CFS.Indeed, his preliminary data demonstrated that in a subgroup of ME/CFS patients with gastrointestinal symptoms there were more antibodies to wheat gluten (this manuscript is in preparation).

Using this preliminary data, Dr. Alaedini proposed a study to further characterize the intestinal immune response in ME/CFS and examine whether it could be associated with bacteria moving across the gut and instigating inflammation. He submitted his application in January 2015 for the NIH ME/CFS funding opportunity (http://grants.nih.gov/grants/guide/pa-f ... 2-033.html) and just received word that he was awarded $200,000 from National Institute of Allergy and Infectious Diseases for this grant!

For too long, research in ME/CFS has been lean and under-funded for several reasons, including the shortage of accurately diagnosed patients available for research studies. The Bateman Horne Center – a clinic specializing in ME/CFS/FM and with a large number of patients who have been carefully and accurately diagnosed, and continue to be treated effectively – will partner with Dr. Alaedini to provide additional well-characterized samples from ME/CFS patients and controls. In addition, we connected Dr. Alaedini with Drs. Sanjay Shukla and Dane Cook. Alaedini will be testing the blood samples Shukla’s team (https://goo.gl/JLdmMa) collected before and after exercise to examine the intestinal immune response and antibodies as biomarkers of post-exertional malaise.

The Bateman Horne Center is committed to bringing ME/CFS and FM into the mainstream of clinical and medical science. Identifying biomarkers is a critical first step. The Bateman Horne Center is a unique example of an independent non-profit integrative health center where medical care informs research, and research informs medical care. We are uniquely positioned to create collaborations between amazing, well-qualified patients and stellar research partners – an important component to progress.

We’ve got a big job to do and we need more patients and researchers involved in research to make objective diagnosis and treatment a reality for all impacted by ME/CFS and Fibromyalgia. Until that day, all “wild sock wearing” feet on deck!

Re: Researchers Find Biological Explanation for Wheat Sensitivity

Alaedini, Armin
Columbia University (N.Y.), New York, NY, United States

Abstract

A major barrier to a better understanding of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has been the heterogeneity within the condition and the lack of biomarkers to characterize disease phenotypes and analyze treatment outcome. While the etiology and pathogenesis of ME/CFS are poorly understood, there is evidence that immune system abnormalities are associated with symptoms in a substantial number of affected individuals. In addition, many ME/CFS patients complain of gastrointestinal (GI) symptoms of unknown etiology. However, immune responses to dietary and microbial antigens as underlying causes of the reported GI symptoms or as contributors to systemic inflammation have not been explored in controlled studies. Our preliminary data from a study of well-characterized patients and controls demonstrate that individuals with ME/CFS exhibit significantly elevated antibody reactivity to gluten, which correlates with the severity of GI symptoms. Moreover, the results show that the observed immune response to gluten in ME/CFS is fundamentally distinct from that in celiac disease, being independent of the action of transglutaminase 2 enzyme and HLA-DQ2/DQ8 molecules. Additional data within this application indicate that increased antibody reactivity to gluten can be associated with microbial translocation in individuals without celiac disease. We hypothesize that the molecular targets of the antibody response to gluten in ME/CFS are unique, further characterization of which may identify novel biomarkers of the condition, and that this immune response is associated with microbial translocation and systemic inflammation in a subset of ME/CFS patients. To analyze the molecular targets of the identified immune reactivity and assess its implications for ME/CFS, we propose two specific aims.

In Aim 1, we will map the antigenic specificity of the immune response to gluten in ME/CFS through mass spectrometry-assisted proteome analysis and epitope mapping.

In Aim 2, we will assess the relationship between the immune response to gluten and specific markers of microbial translocation and systemic inflammation in ME/CFS. The information that is expected to emerge if the aims of the proposed project are achieved would 1) offer biomarkers that may be useful in identifying subsets of patients or individuals at risk of developing ME/CFS, 2) support the examination of specific treatment strategies targeted at the identified subset of patients, and 3) yield experimental support for closer examination of the role of intestinal barrier defects and aberrant mucosal immune response in the pathophysiology of ME/CFS. This grant proposal is in line with the program announcement's (PAR-12-033) request for applications that examine the etiology, diagnosis, pathophysiology, and treatment of chronic fatigue syndrome, such as the identification of environmental, including dietary, precipitants and the development of novel and objective biological markers for the diagnosis of ME/CFS.

Public Health Relevance

ME/CFS is a debilitating and highly heterogeneous condition affecting an estimated one to four million people, mostly women, in the U.S., with a total annual economic burden believed to exceed $18 billion. However, the etiopathology of the disease remains incompletely understood, specific biomarkers have not been identified, and there are no known cures. Our preliminary data demonstrate, for the first time, the presence of an increased antibody response to wheat gluten in a subset of individuals with ME/CFS that is associated with gastrointestinal symptoms. The proposed study represents a systematic approach to assess the relevance of immune reactivity to gluten in ME/CFS by characterizing and mapping its antigenic specificity and by examining its relationship to microbial translocation and systemic inflammation.

Abstract
Background
Celiac disease (CD) is an autoimmune enteropathy triggered by the ingestion of gluten. Gluten-sensitive individuals (GS) cannot tolerate gluten and may develop gastrointestinal symptoms similar to those in CD, but the overall clinical picture is generally less severe and is not accompanied by the concurrence of tissue transglutaminase autoantibodies or autoimmune comorbidities. By studying and comparing mucosal expression of genes associated with intestinal barrier function, as well as innate and adaptive immunity in CD compared with GS, we sought to better understand the similarities and differences between these two gluten-associated disorders.